Could GLP-1 Drugs Lower Heart Attack Risk?
“The signal is compelling," said researchers following new GLP-1 research.
Diabetes and cardiovascular disease are closely linked—people with type 2 diabetes are roughly twice as likely to develop heart disease, and may also be at a higher risk for heart arrhythmias and stroke. Glucagon-like peptide-1 (GLP-1) receptor agonists have gained prominence in the management of diabetes. However, given the range of alternative therapies that also demonstrate clinical benefit, further research is needed to compare treatment options and their value across outcomes.
In a new study, researchers at Brigham and Women’s Hospital found that tirzepatide—a dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist—reduced the one-year risk of major cardiovascular events (MACE) in overweight adults with type 2 diabetes, compared to treatment with sitagliptin—another common diabetes drug. The work was recently published in the BMJ.
The risks of diabetes and the role of GLP-1 medicines
Type 2 diabetes is a condition characterized by elevated blood glucose. If left untreated, excess glucose damages blood vessels, and the reparative process gradually thickens and stiffens blood vessel walls. Eventually, blood flow to body tissues is reduced.
This manifests throughout the body: a patient may experience visual disturbances as the small vessels in their eyes are damaged, the kidneys may fail as their filtering system becomes increasingly dysfunctional, and the peripheries of the limbs may become numb.
Should the heart and brain lack sufficient blood supply, this can lead to chest pain or a transient ischemic attack (also known as a "mini-stroke"). For some, the first manifestation is a fatal heart attack or stroke.
The term MACE encompasses all of these incidents and is used in research to quantify cardio- and cerebrovascular risk. For those with diabetes, MACE risk is significantly higher.
GLP-1 therapies were developed for diabetes; they leverage the body’s innate mechanisms to control blood glucose. GLP-1 drugs have previously been reported to lower MACE risk, but this benefit is not universal across all diabetic medications.
Tirzepatide is a next-generation, dual GLP-1 and GIP receptor agonist. Investigators have previously examined whether tirzepatide improves cardiovascular outcomes compared with sole GLP-1 agonists, but the dual agonist had not been directly compared with a placebo proxy, i.e., a known cardiovascular outcome neutral drug.
MACE risk results require careful interpretation
In the new study, researchers compared tirzepatide with sitagliptin— a common type 2 diabetes treatment which is reported to be cardio-neutral; meaning that it neither significantly increases nor decreases the risk of cardiovascular events.
Sitagliptin
Sitagliptin is a diabetic medication. It works by inhibiting dipeptidyl peptidase-4 (DPP-4). DDP-4 breaks down incretin hormones, such as GLP-1 and GIP. By inhibiting the DDP-4 enzyme, incretin levels are sustained after meals, prolonging beneficial incretin functions such as blood glucose control.
The study used a new-user active comparator design, in which patients initiating tirzepatide were compared with those initiating sitagliptin. Data were collected from two national medical claims databases between 2022 and 2025.
Eligibility criteria included being aged 40 years or older, having a diagnosis of type 2 diabetes, established atherosclerotic cardiovascular disease and/or a history of a vascular event, and a BMI above 25.
The cohort included 52,971 adults, 35,353 of whom commenced tirzepatide, and 17,618 started sitagliptin. Overlap weighting was applied to balance characteristics between the two groups. Analysis ran from treatment initiation until an outcome was met, they were disenrolled from the claims database, or they discontinued their original treatment.
The primary outcome was MACE, a composite of stroke, myocardial infarction, and all-cause mortality. The overlap-weighted 1-year MACE hazard was significantly lower in the tirzepatide treatment group (2.9%) compared to the sitagliptin group (4.4%). This translates to a number needed to treat (NNT) of 70.
Number needed to treat
The NNT is the number of patients who need to receive a given treatment to achieve a beneficial result or prevent a harmful one, such as MACE.
Though the findings appear promising, the researchers cautioned that a nuanced interpretation is needed.
When analyzing the individual components of MACE, tirzepatide was associated with a lower hazard ratio for myocardial infarction, but there was no meaningful difference in the hazard of stroke.
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All-cause mortality saw the largest hazard reduction with tirzepatide use (45%). However, the researchers again cautioned care in interpreting this result. In an exploratory analysis, they found that infection-related death, which falls under all-cause mortality, was significantly lower in the tirzepatide group. Tirzepatide use was also associated with a lower risk of infection-related hospitalization.
“The results were driven primarily by lower hazards of myocardial infarction and all-cause mortality, which were in turn driven by infection-related deaths,” said the study authors.
Identifying new questions in GLP-1 research
“Adding tirzepatide to standard of care was associated with a lower risk of MACE compared with adding a cardiovascular neutral comparator,” said the study authors. The team hopes to encourage informed, shared decision-making between clinicians and patients when considering treatment options.
“Infection-related pathways may account for a substantial share of the observed survival benefit,” they commented, later adding that this cannot be confirmed without further investigation.
Though the research has been described as rigorous, with overlap weighting, past-study benchmarking, and use of a pre-registered trial protocol, it cannot definitively attribute the reduced MACE hazard ratio to tirzepatide in the same way a randomized controlled trial could.
Additionally, the study's findings are based on claims databases, which may contain data errors.
“Future studies should disentangle atherosclerotic from non-atherosclerotic mechanisms underlying tirzepatide’s survival benefit,” concluded the study authors.
Reference: Krüger N, Schneeweiss, S, and Wang SV. Tirzepatide and the risk of atherosclerotic cardiovascular events: population based cohort study. BMJ. 2026. doi: 10.1136/bmj-2026-100011
This article is a rework of a press release issued by the BMJ. Material has been edited for length and content.
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